OBJECTIVETo investigate the effect and potential mechanisms of rutaecarpine (Rut) in a rat artery balloon-injury model.

METHODSThe intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery (CCA) of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut (25, 50 and 75 mg/kg) with 10 rats of each group. The rats were treated with or without Rut (25, 50, 75 mg/kg) by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen (PCNA) and smooth muscle (SM) α-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 (ERK2), MAPK phosphatase-1 (MKP-1) and endothelial nitric oxide synthase (eNOS) were determined by real-time reverse transcription-polymerase chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 (p-ERK2) were examined by Western blotting. The plasma contents of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) were also determined.

RESULTSCompared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury (P<0.05 or P<0.01). The positive expression rate of PCNA was decreased, while the expression rate of SM α-actin obviously increased in the vascular wall after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01). Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated (P<0.05 or P<0.01). The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downregulated after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01), respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma (P<0.05 or P<0.01).

CONCLUSIONRut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.

Actins ; metabolism ; Animals ; Carotid Arteries ; drug effects ; metabolism ; pathology ; Carotid Artery Injuries ; drug therapy ; genetics ; pathology ; Cyclic GMP ; blood ; Disease Models, Animal ; Gene Expression Regulation ; drug effects ; Hyperplasia ; Indole Alkaloids ; pharmacology ; therapeutic use ; Male ; Nitric Oxide ; blood ; Phosphorylation ; drug effects ; Proliferating Cell Nuclear Antigen ; metabolism ; Quinazolines ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley ; Tunica Intima ; drug effects ; pathology

Neointimal proliferation after vascular injury is a key mechanism of restenosis, a major cause of percutaneous transluminal angioplasty failure and artery bypass occlusion. Emodin, an anthraquinone with multiple physiological activities, has been reported to inhibit proliferation of vascular smooth muscle cells (VSMCs) that might cause intimal arterial thickening. Thus, in this study, we established a rat model of balloon-injured carotid artery and investigated the therapeutic effect of emodin and its underlying mechanism. Intimal thickness was analyzed by hematoxylin and eosin staining. Expression of Wnt4, dvl-1, beta-catenin and collagen was determined by immunohistochemistry and/or western blotting. The proliferation of VSMC was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and electron microscopy. MicroRNA levels were quantified by real-time quantitative PCR. Emodin relieved injury-induced artery intimal thickness. Results of western blots and immunohistochemistry showed that emodin suppressed expression of signaling molecules Wnt4/Dvl-1/beta-catenin as well as collagen protein in the injured artery. In addition, emodin enhanced expression of an artery injury-related microRNA, miR-126. In vitro, MTT assay showed that emodin suppressed angiotensin II (AngII)-induced proliferation of VSMCs. Emodin reversed AngII-induced activation of Wnt4/Dvl-1/beta-catenin signaling by increasing expression of miR-126 that was strongly supported by transfection of mimic or inhibitor for miR-126. Emodin prevents intimal thickening via Wnt4/Dvl-1/beta-catenin signaling pathway mediated by miR-126 in balloon-injured carotid artery of rats.
Adaptor Proteins, Signal Transducing/*metabolism ; Animals ; Carotid Arteries/drug effects/metabolism/pathology ; Carotid Artery Injuries/*drug therapy/metabolism/pathology ; Cell Proliferation/drug effects ; Emodin/*therapeutic use ; Male ; MicroRNAs/*metabolism ; Phosphoproteins/*metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Tunica Intima/*drug effects/metabolism/pathology ; Wnt4 Protein/*metabolism ; beta Catenin/*metabolism

OBJECTIVETo study the effect of compound Danshen dripping pills and atorvastatin on restenosis after abdominal aorta angioplasty in rabbits.

METHODSRabbit models of abdominal aorta restenosis after angioplasty were established and treated with saline (group A), compound Danshen dripping pills (group B), atorvastatin (group C), or compound Danshen dripping pills plus atorvastatin (group D). HE staining was used to determine the thickness of arterial intimal hyperplasia and assess the morphological changes of the narrowed artery. Immunohistochemistry was employed to detect the expression of nuclear factor-κB (NF-κB) and monocyte chemoattractant protein-1 (MCP-1).

RESULTSCompared with group A, the 3 treatment groups showed significant increased vascular cavity area and reduced intimal area and percentage of intimal hyperplasia (P<0.05). The vascular cavity area, intimal area and percentage of intimal hyperplasia levels differed significantly between group D and groups B and C (P<0.05). Immunohistochemistry showed a significant reduction of the expression rate of NF-κB and MCP-1 in the 3 treatment groups compared with group A (P<0.05), and the reduction was especially obvious in group D (P<0.05).

CONCLUTIONSCompound danshen dripping pills combined with atorvastatin produces better effects than the drugs used alone in inhibiting vascular smooth muscle cell proliferation in rabbits after abdominal aorta angioplasty possibly due to a decreased expression of MCP-1 as a result of NF-κB inhibition.

Angioplasty ; Animals ; Aorta ; pathology ; Atorvastatin Calcium ; Cell Proliferation ; Chemokine CCL2 ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Heptanoic Acids ; pharmacology ; Hyperplasia ; Myocytes, Smooth Muscle ; drug effects ; NF-kappa B ; metabolism ; Phenanthrolines ; Pyrroles ; pharmacology ; Rabbits ; Salvia miltiorrhiza ; chemistry ; Tunica Intima

Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to vascular injury such as angioplasty. Protein kinase G (PKG) has an important role in the process of VSMC phenotype switching. In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, could modulate VSMC phenotype through the PKG pathway to reduce neointimal hyperplasia after angioplasty. In vitro experiments showed that rosiglitazone inhibited the phenotype change of VSMCs from a contractile to a synthetic form. The platelet-derived growth factor (PDGF)-induced reduction of PKG level was reversed by rosiglitazone treatment, resulting in increased PKG activity. This increased activity of PKG resulted in phosphorylation of vasodilator-stimulated phosphoprotein at serine 239, leading to inhibited proliferation of VSMCs. Interestingly, rosiglitazone did not change the level of nitric oxide (NO) or cyclic guanosine monophosphate (cGMP), which are upstream of PKG, suggesting that rosiglitazone influences PKG itself. Chromatin immunoprecipitation assays for the PKG promoter showed that the activation of PKG by rosiglitazone was mediated by the increased binding of Sp1 on the promoter region of PKG. In vivo experiments showed that rosiglitazone significantly inhibited neointimal formation after balloon injury. Immunohistochemistry staining for calponin and thrombospondin showed that this effect of rosiglitazone was mediated by modulating VSMC phenotype. Our findings demonstrate that rosiglitazone is a potent modulator of VSMC phenotype, which is regulated by PKG. This activation of PKG by rosiglitazone results in reduced neointimal hyperplasia after angioplasty. These results provide important mechanistic insight into the cardiovascular-protective effect of PPARgamma.
Animals ; Aorta/injuries/metabolism/*pathology ; Calcium-Binding Proteins/genetics/metabolism ; Cell Proliferation ; Cyclic GMP/metabolism ; Cyclic GMP-Dependent Protein Kinases/genetics/*metabolism ; Hyperplasia/metabolism ; Microfilament Proteins/genetics/metabolism ; Muscle, Smooth, Vascular/metabolism/pathology ; Myocytes, Smooth Muscle/drug effects/*metabolism ; Nitric Oxide/metabolism ; PPAR gamma/agonists/*metabolism ; Promoter Regions, Genetic ; Rats ; Rats, Sprague-Dawley ; Sp1 Transcription Factor/metabolism ; Thiazolidinediones/pharmacology ; Thrombospondins/genetics/metabolism ; Tunica Intima/metabolism/*pathology ; Vascular System Injuries/*metabolism/pathology

OBJECTIVETo observe the effects of Tongguan Capsule on the mobilization and differentiation of bone marrow mononuclear cells (BMMNCs) to the injured carotid arteries.

METHODSThe rat model of injured carotid arteries was established. Mononuclear cells were separated from the bone marrow of donor rats, which were labeled by PKH 26 and then injected through the tail vein to the recipient rats with injured carotid arteries. The rats were randomly divided into two groups. Tongguan Capsule suspension was administered by gastrogavage to rats in the experiment group, while equal volume of normal saline was given to rats in the control group. Four weeks later the injured carotid arteries were harvested and frozen sections were made to observe the differences of intima area/media area ratio (Ai/Am). The difference of BMMNCs migrating to the injured carotid arteries between the two groups was observed under fluorescence microscope. The difference of the vascular endothelial growth factor (VEGF) and stromal derived factor-1 (SDF-1) levels in serum were detected by ELISA.

RESULTSThe PKH 26 labeled cells appeared in the experiment group, while only little scattered fluorescent light points was presented in the control group. The intima area and the ratio of Ai/Am of the experiment group decreased more obviously than that of the control group (P<0.01). Two and 4 weeks later the VEGF and SDF-1 levels in serum of the experiment group were more obviously enhanced than those of the control group (P<0.01).

CONCLUSIONTongguan Capsule could promote the BMMNCs transplanting towards the intima of injured carotid arteries, and take part in the repair of the intima of injured carotid arteries.

Animals ; Bone Marrow Cells ; cytology ; Cell Differentiation ; drug effects ; Chemokine CXCL12 ; blood ; Drugs, Chinese Herbal ; pharmacology ; Endothelium, Vascular ; Monocytes ; cytology ; drug effects ; Rats ; Rats, Wistar ; Tunica Intima ; cytology ; drug effects ; pathology ; Vascular Endothelial Growth Factor A ; blood

OBJECTIVETo evaluate neointimal proliferation following placement of a new drug-eluting stent (BUMA) by optical coherence tomography (OCT).

METHODSTwenty-two patients with coronary artery disease were randomized into BUMA group (n=15) and Endeavor group (n=7) and underwent OCT imaging after 9 months of stent implantation.

RESULTSThe neointima hyperplasia (NIH) thickness in BUMA group were significantly smaller than that in endeavor group (0.220-/+0.140 mm vs 0.269-/+0.207 mm, P<0.001), and the uncovered Struts were significantly lower in BUMA group than in Endeavor group (5.65% vs 6.56%, P<0.0001). The luminal late loss in BUMA group was also significantly lower (34.87-/+11.50 vs 40.82-/+18.53, P=0.025).

CONCLUSIONBUMA stent is safe and effective for treatment of coronary artery disease.

Angioplasty, Balloon, Coronary ; adverse effects ; Cell Proliferation ; Coronary Artery Disease ; pathology ; therapy ; Coronary Vessels ; pathology ; Drug-Eluting Stents ; adverse effects ; Humans ; Prospective Studies ; Tomography, Optical Coherence ; Tunica Intima ; pathology

OBJECTIVETo study the safety and efficacy of control-releasing arsenic trioxide (As2O3)-eluting stent on intimal smooth muscle cells (SMC) and type III collagen (CIII) in canine coronary artery post-stent model.

METHODSTwenty-four experimental canines were equally divided into 4 groups, the three tested groups were deployed by stents with different dosage of As2O3 (1.6 microg/mm2, 2.4 microg/mm2 and 3.2 microg/mm2 in low, median and high dose groups, respectively) and coated with polybutyl methacrylate/nano silica and poly-lactide-coglycolide in mild oversizing (stent/vessel ratio of 1.3:1) in left anterior descending (LAD) or circumflex coronary arteries (LCX), while the control group only by simple coated stent without As2O3. The effect was assessed 4 weeks after stent implantation in terms of vascular histomorphology, and changes of SMC and C III expressions were detected using immunohistochemical analysis.

RESULTSSubintimal hemorrhage, medial/adventitial necrosis, thrombosis and inflammatory cell infiltration were not found and integral endothelium could be seen under screening electron microscopy in all groups. Positive expression of SMC and CIII in the tested groups, especial in the high dose As2O3 group, was more weaker than that in control group. Histo-morphological analysis showed that the neo-genetic intimal area and vascular stenosis were lower, but the mean luminal diameter was larger in the three tested groups than that in the control group (P < 0.01). Comparisons of various indices between tested groups treated by different doses of As2O3 showed that the difference between high/median dose vs. low dose was significant (P < 0.01), but that between high dose vs. median dose was insignificant (P > 0.05).

CONCLUSIONControl-releasing As2O3-eluting stent shows a reliable and safe effect in preventing and treating post-stent restenosis by its dose-dependent inhibition on expressions of SMC and CIII to suppress the neo-genesis of intimal hyperplasia.

Animals ; Arsenicals ; administration & dosage ; pharmacology ; Collagen Type III ; metabolism ; Coronary Restenosis ; etiology ; prevention & control ; Coronary Vessels ; metabolism ; pathology ; Dogs ; Drug-Eluting Stents ; Female ; Implants, Experimental ; Male ; Muscle, Smooth, Vascular ; drug effects ; metabolism ; pathology ; Oxides ; administration & dosage ; pharmacology ; Tunica Intima ; drug effects ; pathology

OBJECTIVETo study the relationship between inflammation and neointimal proliferation after coronary stent implantation in porcine model.

METHODSTwenty normal minipigs were randomly divided into group A (implanted with 316L bare metal stents), group B (implanted with 605L bare metal stents), group C (implanted with PLGA coating 605L stents), and group D (implanted with rapamycin-loaded PLGA coating 605L stents). Each minipig was implanted with two same stents in left anterior descending artery and right coronary artery. Four weeks later, the animals were sacrificed and histomorphometric measurements on the stent-segment coronary arteries were made to calculate the correlation between inflammation area and neointimal area.

RESULTSGroup D had the smallest neointimal area [(0.64 +/- 0.38) mm2, P < 0. 001] and inflammation area (median 0.00 mm2, P = 0.009) among all the groups, while there were no statistical differences among group A, B, and C in neointimal area [(2.09 +/- 0.90), (2.11 +/- 1.07), and (1.42 +/- 0.35) mm2 respectively] and in inflammation area (0.22 , 0.21, and 0.09 mm2, respectively). Bivariate correlation analysis showed that the inflammation area was positively correlated with the neointimal area (P < 0.001, correlation coefficient = 0.719). When stent type, mean injury score, and EEL area were adjusted, partial correlations analysis showed that the inflammation area was still positively correlated with the neointimal area (P = 0.01, correlation coefficient = 0.498).

CONCLUSIONInflammation promotes the neointimal proliferation after coronary stent implantation. Sirolimus-eluting stent may reduce the inflammatory response.

Animals ; Coronary Vessels ; pathology ; Drug-Eluting Stents ; adverse effects ; Inflammation ; pathology ; Neointima ; pathology ; Stents ; adverse effects ; Swine ; Swine, Miniature ; Tunica Intima ; pathology

OBJECTIVETo explore the effect and the mechanism of panax notoginseng saponins (PNS) on the vascular intima hyperplasia and expression of proliferating cell nuclear antigen (PCNA) after aortic intima injury induced ballcon in rats.

METHODModel of aortic intima denudation in rats was established by 2.0 forgarty. The rats were randomly divided into sham group, model group, PNS group and atorvastatin group. Drugs were administered at the second day after the aortic intima injury for 14 days. The injured thoracic aorta segment were taken to detected the vascular morphological changes and expression of PCNA by histomorphology and immunohistochemic methods.

RESULTThe intimal area (IA), intimal thickness (IT), hyperplasia ratio of intimal area (HRIA), the ratio of intimal/mesolamella area and thickness in the model group were significantly higher than those of the sham operation (P<0.01). The above indexes in PNS and atorvastatin group were markedly lower than those in the model group (P<0.05). Compared with the sham group, the expression of PCNA in the model was enhanced remarkably (P<0.01). Compared with the model group, the expression of PCNA in PNS and atorvastatin group was significantly lowered (P<0.01).

CONCLUSIONPNS could inhibit intima hyperplasia by inhibiting proliferation of the vascular smooth muscle cell after vascular intima injury.

Angioplasty, Balloon, Coronary ; Animals ; Aorta ; drug effects ; metabolism ; pathology ; Cell Proliferation ; drug effects ; Gene Expression Regulation ; drug effects ; Hyperplasia ; drug therapy ; metabolism ; pathology ; therapy ; Male ; Panax notoginseng ; chemistry ; Proliferating Cell Nuclear Antigen ; metabolism ; Rats ; Saponins ; administration & dosage ; pharmacology ; therapeutic use ; Tunica Intima ; drug effects ; metabolism ; pathology

BACKGROUND/AIMS: Recent intravascular ultrasound (IVUS) studies of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) have demonstrated a significant reduction in neointimal hyperplasia (NIH) based on simple coronary lesions. In this study, we evaluated the efficacy of SES and PES using IVUS in complex coronary lesions. METHODS: Eighty-seven patients in whom 95 drug-eluting stents (66 SES and 29 PES) were implanted in complex coronary lesions were enrolled in this study. Case selection was based on the availability of IVUS and quantitative coronary angiographic (QCA) examinations at the index procedure and at follow-up. The neointimal volume index (volume/length: NIVI) and percent neointimal volume (% NIV) were calculated. The longitudinal length of stented segments without IVUS-detectable NIH was also evaluated. RESULTS: The baseline patient demographics were similar between the SES and PES groups. At follow-up, no significant differences were observed in the vessel, plaque, or stent volume indices between the two groups. However, the NIVI and % NIV were significantly lower in the SES group (p<0.01). The longitudinal length of stented segments without IVUS-detectable NIH was significantly higher in the SES group (p<0.01). The net gain was significantly larger in the SES group (2.3+/-0.7 vs. 2.0x0.6 mm, p=0.025), while the rate of major adverse cardiac events was similar between the two groups. CONCLUSIONS: Although SES showed significantly greater suppression of NIH at follow-up, both stents were highly effective at inhibiting NIH in complex coronary lesions.
Adult ; Aged ; Coronary Angiography ; Coronary Artery Disease/radiography/*therapy/ultrasonography ; *Drug-Eluting Stents/adverse effects ; Female ; Follow-Up Studies ; Humans ; Hyperplasia ; Male ; Middle Aged ; Paclitaxel/*administration & dosage ; Sirolimus/*administration & dosage ; Tunica Intima/pathology ; Ultrasonography, Interventional/*methods